The present invention refers to the use of agents for blocking the synthesis of tyrosinase to prevent permanent pigmentation of the iris caused by melanin deposit induced by pharmacological treatments or by metabolic imbalance.
Latanoprost (13,14-dihydro-17-phenyl-18,19,20-tri- nor-PGF2xcex1isopropyl ester), a synthetic prostaglandin analogue, (EP-A-0364317) as well as naturally occurring prostaglandins such as PGF2xcex1 and PGE2 have been shown to induce increased pigmentation of the monkey iris during chronic treatment (Selxc3xa9n G., Stjernschantz J., Resul B. prostaglandin-induced iridial pigmentation in primates. Surv. Ophthalmol 1997; 41, Suppl. 2: S125-S128). The exact mechanism behind this response to prostaglandin treatment is not known, but increased synthesis of melanin (melanogenesis) must occur for the eye colour to become darker. Also in patients treated with latanoprost (Wistrand P J, Stjernschantz J., Olsson K. The incidence and time-course of latanoprost-induced iridial pigmentation as a function of eye color. Surv. Ophthalmol 1997; 41, Suppl. 2:S129-S138) or with isopropyl unoprostone (13,14-dihydro-15-keto-20-ethyl-PGF2xcex1 isopropylester) (Yamamoto T., Kitazawa Y. Iris-color change developed after topical isopropyl unoprostone treatment J. Glaucoma 1997; 6: 430-432) a darkening of the iris is sometimes noted during chronic therapy. Particularly patients with heterochromic iris, i.e. blue-brown, gray-brown, green-brown or hazel eye colour seem to be predisposed to this side-effect. Since the side-effect may become cosmetically disturbing, particularly in patients with unilateral glaucoma that are treated only in one eye, and since the side-effect is irreversible, and relatively frequent, it would be advantageous to circumvent it, although it does not appear to pose a health hazard to the patients that develop it.
Melanin, a large naturally occurring polymer is formed from the amino acid tyrosine. In the initial step of melanin formation tyrosine is hydroxylated to L-Dopa which is further oxidized to dopaquinone. The enzyme catalyzing both reactions is called tyrosinase. Dopaquinone is a labile compound that is converted to dopachrome, a black compound which is needed for the formation DHICA (dihydroxyindol-carboxylic acid) oligomers that are needed for the final polymerisation to yield eumelanin (black or brown melanin). Dopaquinone can alternatively react with cysteine which will lead to sulfur containing oligomers and finally pheomelanin (yellowish or reddish melanin). Important to realize is that the rate limiting step in the melanin production is the reaction catalyzed by tyrosinase. Lack of functional tyrosinase e.g. because of a mutation of the tyrosinase gene, always leads to albinism since no pigment can be formed in the body. Interestingly, the same tyrosinase enzyme is also needed in sympathetic neurons and adrenal medulla for the production of noradrenaline, a neurotransmitter, and adrenaline, a hormone, since these compounds are biosynthetized from tyrosine. Thus compounds that block the tyrosinase enzyme will have effect both on melanogenesis and on the function of the sympathetic nervous system.
It has now been found that inhibitors of the tyrosinase enzyme, particularly, xcex1-methyl-p-tyrosine, inhibit melanin production induced by administration of PGF2xcex1, and PGE2 derivatives, such as latanoprost and unoprostone.
Thus, the treatment with said tyrosinase inhibitors prior, during or after administration of prostaglandin derivatives in glaucomatous patients, inhibits melanin production by iris melanocytes avoiding the eye coloring variations in these patients.